Induction and maintenance of immunological tolerance to the transplanted tissue is essential for allograft survival. The main goal of this Program Project is to develop tolerance induction protocols employing NK cell and costimulation blockades that will enhance graft survival by suppressing both innate and adaptive immune responses to the engrafted tissue. However, a major concern is how these tolerance induction protocols will effect immune response to pathogens. This issue is of considerable significance since opportunistic viral infections are a major complication of transplantation. Project #4 will examine the effects of T cell co- stimulatory and NK cell blockade on protective immunity to viruses. This question will be addressed using two well characterized models of viral infections; (i) murine cytomegalovirus (MCMV) which serves as a model for human CMV infections and (ii) lymphocytic choriomeningitis virus (LCMV) which is the classic model for analyzing antiviral T cell immunity. The goals of this proposal are three-fold: first, to define the basic co- stimulatory requirements for inducing antiviral protective immunity; second, to see how these rules hold up in a transplant setting; and third, to determine if the virus infection, by itself, can modulate the transplantation tolerance induction protocols and effect graft survival. Successful transplantation requires the right balance between suppressing immune responses to the graft but still allowing the host to control opportunistic infections. The proposed studies should provide insight into developing tolerance induction protocols that provide such a balance.